Equity research - Jerónimo Martins SGPS, SA

Mestrado Bolonha em FinançasThe main objective of this equity research project is to estimate the price target of Jerónimo Martins, based on cash flow forecasts. Jerónimo Martins is one of the largest Portuguese companies in the food retail sector, with sales in 2021 of more than € 20 billion. The forecast covers the period from 2022 to 2027 and is based on the past performance of the company, from 2017 to 2021. The study begins with a snapshot of the history of the company and its corporate governance and, then, provides an overview of the Jerónimo Martins´ business and industry. It also contains a SWOT analysis, a PESTEL analysis, and a Porter 5 Forces analysis. A financial analysis is conducted highlighting the outlook for key financial ratios. To reach the target value for 2023, two main valuation models are employed. The absolute model includes the Discounted Cash Flow (DCF), the Adjusted Present Value (APV), the Economic Value Added (EVA), and the Dividend Discount Model (DDM). The relative model is based on a comparison of the company's main indicators with those of the chosen peer group. Subsequently, a risk matrix is used to consider the Jerónimo Martins´ risks. Ultimately, other analyses are considered, namely, the Scenario and Sensitivity Analysis, as well as the Monte Carlo simulation. The final investment recommendation is Hold, with a price of € 24,28, an upside of 10,17 % from the price of September 5, 2022. It is considered a medium risk investment.O principal objetivo deste projeto de equity research é estimar o preço da ação da Jerónimo Martins, com base nas previsões de cash flow. A Jerónimo Martins é uma das maiores empresas portuguesas do setor do retalho alimentar, com vendas em 2021 superiores a 20 mil milhões de euros. A previsão considerada abrange o período de 2022 a 2027 e tem como base o desempenho passado da empresa, de 2017 a 2021. O estudo começa com um resumo da pesquisa, um histórico da empresa, a sua governança corporativa e inclui ainda uma visão geral dos seus negócios e do setor. É igualmente feita uma análise SWOT, uma análise PESTEL e uma análise Porter 5 Forces. Também foi realizada uma análise financeira destacando as perspetivas para os principais índices financeiros. Para atingir o valor alvo para 2023, foram realizados dois principais modelos de avaliação. O modelo absoluto, que inclui o Fluxo de Caixa Descontado (FCD), o Valor Presente Ajustado (APV), o Valor Económico Adicionado (EVA) e o Modelo de Desconto de Dividendos (DDM). Também foi realizado o modelo relativo, comparando os principais indicadores da empresa com um grupo com características semelhantes. Posteriormente, foi utilizada uma matriz de riscos para considerar os riscos organizacionais. Por fim, outras análises foram consideradas, a Análise de Cenário e Sensibilidade, bem como a simulação de Monte Carlo. A recomendação final de investimento é Hold, com preço de € 24,28, uma valorização de 10,17 % em relação ao preço alvo de 5 de setembro de 2022. É considerado um investimento de médio risco.info:eu-repo/semantics/publishedVersio

Role of Wnt signaling in heart disease

Dissertação de mestrado em Molecular GeneticsHeart failure has a major social-economic impact in our society. Despite major advances in the understanding of this pathology, the mechanisms of its development, as well as its pathophysiology, remain unclear. Therefore, it is our priority to clarify how extra- and intracellular factors are able to modulate heart function. Several pathways and/or factors had already been associated with different phases of heart failure development namely TGF-β, IGF, calcineurin, several GPCRs, MAPK, Akt and GSK-3. More recently, several studies started shedding some light on a putative role of Wnt signaling in heart failure development. Wnt signaling is a major regulator of cell-fate specification during development, proliferation, survival, migration and adhesion. Several diseases including cancer, diabetes, osteoporosis and psychiatric disorders are the result of deregulation of canonical Wnt signaling, due to either genetic alterations or changes in the levels of its effectors. The role of canonical Wnt signaling in heart development is well established and it has been shown to be biphasic, in the sense that its activation is initially required for the commitment of cells to a cardiac lineage and in its inhibition, cardiogenesis is triggered. In heart failure development, a possible role for Wnt signaling has only recently been reported, yet, its results are contradictory. Nonetheless, it was not addressed a possible role exerted by extracellular modulators and receptors of the Wnt pathway. Because of its role in the development of other diseases, and since its extracellular and membrane effectors are regarded as potential targets of pharmacological intervention in the treatment of such pathologies, it became imperative the understanding of Wnt signaling regulation in heart disease and how these interventions would affect heart function. Taking these facts into account, our first goal was to perform a detailed gene expression analysis of different Wnt ligands, receptors and co-receptors, during heart disease development in a type 1 diabetes mellitus rat model. Since in other contexts, Wnt signaling interacts with other pathways known to present a role in the development of diabetic heart disease, such as PPARs and FOXO proteins, we also checked their expression levels. With this approach we aimed starting to unveil a possible role for Wnt signaling in heart disease development as well as possible interactions with other pathways, known to be important of this pathology.A insuficiência cardíaca apresenta um impacto socioeconómico grande na nossa sociedade. Apesar de grandes avanços na compreensão desta patologia, os mecanismos do seu desenvolvimento, assim como a sua fisiopatologia, permanecem obscuros. De tal forma, é nossa prioridade o esclarecimento de como factores extra- e intracelulares são capazes de modular a função cardíaca. Diversas vias e/ou factores já foram associados a diferentes fases do desenvolvimento de insuficiência cardíaca, nomeadamente TGF-β, IGF, calcineurina, várias GPCRs, MAPK, Akt e GSK-3. Mais recentemente, vários estudos sugerem/apontam um potencial papel da via dos Wnts, no desenvolvimento de insuficiência cardíaca. A via das Wnts é um importante regulador do desenvolvimento, proliferação, sobrevivência e adesão celulares. Várias doenças como cancro, diabetes, osteoporose e disfunções psiquiátricas, são o resultado da desregulação da via canónica das Wnts, devido a alterações genéticas ou alterações a nível celular dos seus factores. A sua função no desenvolvimento cardíaco é bem conhecida e revelou-se bifásica, já que, inicialmente, a sua activação é necessária para diferenciação numa linhagem cardíaca e posteriormente, a sua inibição activa a cardiogénese. Vários estudos sugerem um potencial envolvimento da via das Wnts na insuficiência cardíaca, no entanto, os seus resultados são contraditórios. Assim, não foi possível identificar o papel desempenhado por moduladores extracelulares e receptores desta via. Devido ao seu papel no evoluir de outras doenças, e porque os seus receptores são potenciais alvos de intervenções farmacológicas no tratamento de tais patologias, tornou-se indispensável o conhecimento da via das Wnts na doença cardíaca e como essas intervenções poderão afectar o coração. Assim, o nosso primeiro objectivo passou por realizar uma análise à expressão genética dos vários ligandos, receptores e co-receptores, durante o desenvolvimento da doença cardíaca num modelo de rato com diabetes tipo 1. Dado que em outros contextos a via das Wnts interagir com outras vias conhecidas por deterem um papel no desenvolvimento da cardiomiopatia diabética, tais como PPARs e FOXOs, também analisamos os seus níveis de expressão. Com esta abordagem, pretendemos revelar o potencial papel da via das Wnts na fisiopatologia da doença cardíaca, assim como, possíveis interacções com outras vias relevantes e associadas a esta patologia

Novel Perspectives in Management of Angiogenesis and Cancer Therapy

Funding: The project was funded by IPOLFG EPE and by iNOVA4Health (UID/Multi/04462/2019) a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds. We also acknowledge funding from FCT-MCTES through the project DREAM—PTDC/MEC-ONC/29327/2017. FL-C PhD fellowship was funded by FCT (PD/BD/128337/2017).The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.publishersversionpublishe

Metabolic changes in hypertrophic cardiomyopathies : Scientific update from the Working Group of Myocardial Function of the European Society of Cardiology

JV is supported by the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2014-40 DOSIS. SH has received funding from the European Union Commission’s Seventh Framework programme under grant agreement N° 305507 (HOMAGE), N° 602904 (FIBROTARGETS) and FP7-Health-2013- Innovations-1 N° 602156 (HECATOS). . We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2011-ARENA, CVON2016-Early HFPEF, and ShePREDICTS. This research is cofinanced as a PPP-allowance Research and Innovation by the Ministry of Economic Affairs within Top Sector Life sciences & Health. This research was co-funded by the C3 project “Vision Core Leuven” of the Leuven UniversityPeer reviewedPublisher PD

Risk factors for infection, predictors of severe disease, and antibody response to COVID-19 in patients with inflammatory rheumatic diseases in Portugal: a multicenter, nationwide study

Copyright © 2022 Cruz-Machado, Barreira, Bandeira, Veldhoen, Gomes, Serrano, Duarte, Rato, Miguel Fernandes, Garcia, Pinheiro, Bernardes, Madeira, Miguel, Torres, Bento Silva, Pestana, Almeida, Mazeda, Cunha Santos, Pinto, Sousa, Parente, Sequeira, Santos, Fonseca and Romão. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Objective: To identify risk factors for SARS-CoV-2 infection and for severe/critical COVID-19, and to assess the humoral response after COVID-19 in these patients. Methods: Nationwide study of adult patients with inflammatory RMDs prospectively followed in the Rheumatic Diseases Portuguese Register-Reuma.pt-during the first 6 months of the pandemic. We compared patients with COVID-19 with those who did not develop the disease and patients with mild/moderate disease with those exhibiting severe/critical COVID-19. IgG antibodies against SARS-CoV-2 were measured ≥3 months after infection and results were compared with matched controls. Results: 162 cases of COVID-19 were registered in a total of 6,363 appointments. Patients treated with TNF inhibitors (TNFi; OR = 0.160, 95% CI 0.099-0.260, P < 0.001) and tocilizumab (OR 0.147, 95% CI 0.053-0.408, P < 0.001) had reduced odds of infection. Further, TNFi tended to be protective of severe and critical disease. Older age, major comorbidities, and rituximab were associated with an increased risk of infection and worse prognosis. Most patients with inflammatory RMDs (86.2%) developed a robust antibody response. Seroconversion was associated with symptomatic disease (OR 13.46, 95% CI 2.21-81.85, P = 0.005) and tended to be blunted by TNFi (OR 0.17, 95% CI 0.03-1.05; P = 0.057). Conclusions: TNFi and tocilizumab reduced the risk of infection by SARS-CoV-2. Treatment with TNFi also tended to reduce rates of severe disease and seroconversion. Older age, general comorbidities and rituximab were associated with increased risk for infection and worse prognosis, in line with previous reports. Most patients with RMDs developed a proper antibody response after COVID-19, particularly if they had symptomatic disease.We acknowledge the generous sharing of the expression constructs by Dr. Florian Krammer, Icahn School of Medicine at Mount Sinai, New York, USA [Development of SARS-CoV-2 reagents was partially supported by the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract HHSN272201400008C] and the protein production by Drs. Paula Alves and Rute Castro at Instituto de Biologia Experimental e Tecnológica (iBET) Oeiras, Portugal as part of the Serology COVID consortium.info:eu-repo/semantics/publishedVersio

Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness

Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+-handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathologicallevels of ADP and diastolic [Ca2+] revealed a 76±1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+- overload. In isolated Langendorff-perfused rat hearts, CK-inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges even at low Ca2+ and thereby increase myocardial stiffness

Mitochondrial Mutations in Subjects with Psychiatric Disorders

A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA

Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation

The research was funded by iNOVA4Health UID/Multi/04462, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência (FCT-MCTES), through national funds, and co-funded by FEDER under the PT2020 Partnership Agreement. We also acknowledge funding from FCT-MCTES through project DREAM PTDC/MEC-ONC/29327/2017.Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H2S-synthesizing enzyme cystathionine β-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H2S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PUREG4-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PUREG4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.publishersversionpublishe

Habitat specificity of a threatened and endemic cliff-dwelling halophyte

Research ArticleCoastal areas and other saline environments are major contributors to regional and global biodiversity patterns. In these environments, rapidly changing gradients require highly specialized plants like halophytes. In European coastal cliff-tops, rocky and sandy seashores, and saltmarshes, typical halophytes from the genus Limonium are commonly found. Among them, the aneuploid tetraploid (2n ¼ 4x ¼ 35, 36, 37) Limonium multiflorum, endemic to the west coast of Portugal, is an interesting case study for investigating the ecology and conservation of a halophyte agamospermic species. Although it is listed in the IUCN red list of threatened species, information on its population size or rarity, as well as its ecology, in some respects is still unknown. Field surveys in the largest known population were performed (Raso cape, Portugal) in order to determine habitat requirements and conservation status. A total of 88 quadrats were monitored, 43 of which contained at least one L. multiflorum individual. For each sampled quadrat, four abiotic and four biotic variables as well as two spatially derived variables were recorded. Principal component analysis and cluster analysis showed narrow habitat specificity for this species which appeared to be intolerant to competition with invasive alien plants. We conclude that in situ conservation in a local ‘hotspot’ of this rare and vulnerable species emerges as a priority in order to ensure that biodiversity is not los